Application progress of Chinese medicine in the treatment of irritable bowel syndrome based on the brain-gut axis theory

Guo-Ying Liang, Jin-Feng Liu, Yi-Bo Wu

1. The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine,Harbin 150040,China

2. Heilongjiang University of Traditional Chinese Medicine,Harbin 150040,China

3. Heilongjiang Academy of Traditional Chinese Medicine,Harbin 150036,China

Keywords:Irritable bowel syndrome Brain-gut axis Brain-gut peptide Traditional Chinese medicine

ABSTRACT Irritable bowel syndrome is one of the most common functional gastrointestinal diseases,with a global prevalence of about 12% [1]. Modern studies have shown that the abnormality of brain-gut peptides is closely related to the occurrence of irritable bowel syndrome. This article starts with vasoactive intestinal peptide, substance P, serotonin, neuropeptide Y, corticotropin releasing factor, calcitonin gene-related peptide, cholecystokinin and other brain-gut peptides and their correlation with intestinal flora, to summarize the treatment of irritable bowel syndrome with traditional Chinese medicine in recent years.

Irritable Bowel Syndrome ( IBS ) is a chronic functional bowel disease with recurrent abdominal pain accompanied by abnormal bowel movements or changes in bowel habits [2]. It is clinically based on stool characteristics and its proportion. Different IBS is divided into four subtypes: diarrhea type ( IBS-D ), constipation type ( IBS-C ), mixed type and indeterminate type. In my country,IBS-D is the most common clinically [3]. It is generally believed that the basic characteristics of the pathophysiology of IBS are mainly immune activation, increased intestinal permeability, abnormal structure and function of enteric nerves, and imbalance of intestinal flora [4], involving the two-way interaction of the brain-gut axis between the brain and the intestine The role of the microbiota and the communication between the intestine and the brain through the microbe-gut-brain axis [5]. Studies have shown that in this process, the changes in brain-gut peptide levels are closely related to the occurrence and development of IBS. Therefore, from the perspectives of brain-gut axis, microbe-gut-brain axis and brain-gut peptide, The traditional Chinese medicine treatment of IBS in recent years is summarized as follows:

1. IBS and brain-gut axis

The gastrointestinal tract has a system that independently regulates the digestion and absorption functions of the intestine, which is called the Enteric Nervous System ( ENS ). The gastrointestinal tract and the central nervous system ( CNS ) are interconnected by nerve fibers and nerve media. This interaction is called "gutbrain interaction", which is based on the neuro-endocrine network mechanism "brain-gut axis" to achieve this, this axis includes the efferent and afferent branches of the autonomic nervous system, circulating endocrine hormones and immune factors, local paracrine and neurosecretory factors, and microbial metabolites [6].Gastrointestinal dysfunction caused by ENS dysfunction may not only lead to abnormal gastrointestinal function, but also may involve cognitive and emotional disorders [7]. The Rome IV [3] standard emphasizes the importance of neurogastroenterology and abnormal brain-gut interaction in the pathogenesis of IBS.

2. IBS and microbe-gut-brain axis

IBS is a disease with changes in the brain-gut-microbiota.Imbalance of the intestinal microflora is increasingly considered as a key part of its pathogenesis. Experimental and clinical reports of IBS indicate that changes in the gut microbiota can affect the morphology of the brain. Function has an impact [8]. Through the treatment of the intestinal microbiota, the level of brain-gut peptides in patients with IBS can be significantly adjusted, and the regulation of the brain-gut axis can be affected, thereby improving the typical clinical symptoms of IBS [9].

3. Brain-gut peptide

Brain-Gut Peptide ( BGP ) is a small molecular peptide, which is distributed in the CNS, ENS and gastrointestinal tract. It can be used as a neurotransmitter to transmit information, and it can also be used as a hormone to perform dual functions to realize brain- Gut interaction. In recent years, the use of traditional Chinese medicine to treat IBS is effective and has a certain regulatory effect on the level of brain-gut peptides. Taking brain-gut peptide as a reference indicator for the treatment of this disease, the pathophysiological link of traditional Chinese medicine intervention in IBS was explored, It is helpful to clarify the mechanism of traditional Chinese medicine treatment of IBS through this way.

3.1 Vasoactive intestinal peptide VIP

VIP is one of the important brain-gut peptides and peptide neurotransmitters. It is called vasoactive peptide because of its strong effect on peripheral and visceral vasodilation. As an important regulator of gastrointestinal smooth muscle, VIP can make the stomach empty. Prolong the time, participate in colon expansion activities, and promote the secretion of pancreatic juice and intestinal juice. Many studies have shown that the expression of VIP in the plasma and intestinal mucosa of IBS patients is increased [9].

3.2 Substance P SP

SP is the first neuropeptide discovered. It has the functions of strong contraction of smooth muscle, contraction of the intestine,increase intestinal motility, relaxation of blood vessels, participation in visceral pain perception and transmission, etc. Because SP is involved in the complex form of intestinal regulation, some studies have found that SP is in IBS The content of rat plasma, duodenum and hypothalamus is relatively high [11], and the experimental research results of some scholars show low changes [12], so the specific changes of its content need to be further experimentally studied.

3.3 Serotonin 5-HT

5-HT is a kind of brain-gut peptide, which is an important neurotransmitter and vasoactive substance in the human body.About 90% of 5-HT in the human body exists in the mucosa of the gastrointestinal tract and participates in regulating the peristaltic reflex. Endogenous 5-HT is closely related to stress-stimulated gastrointestinal reactions and can cause visceral hypersensitivity reactions [13]. Studies have found that there is 5-HT in the distal colon of IBS rats, which affects the frequency of defecation and changes in stool shape [14].

3.4 Neuropeptide Y NPY

NPY can combine with peripheral acetylcholine transferase in submucosal ganglia in the enteric nerve plexus, and inhibit gastrointestinal sensation, movement, secretion, and absorption.In the hippocampus and hypothalamus, it participates in central antagonistic stress response and stability The role of emotions [15].There is an increase in the content of NPY in the colonic mucosa of IBS patients, which is involved in the occurrence and development of the disease [16].

3.5 Corticotropin releasing factor CRF

CRF is the most important regulator to promote adrenal cortex hormones. The stress response can promote the synthesis and secretion of CRF. When the hypersensitivity colon sensory receptors are abnormally excited, the CRF nerves in the paraventricular nucleus and locus coeruleus of the hypothalamus are excited, which can cause changes in mental behavior, high movement and watery of the colon diarrhea [17].

3.6 Calcitonin gene-related peptide CGRP

CGRP is a polypeptide substance, which has the functions of dilating endogenous blood vessels, inhibiting gastrointestinal movement and regulating visceral pain. The release of CGRP from sensory neurons can be caused by gastrointestinal mucosal damage and stimulation. CGRP can directly bind to the CGRP receptor on the surface of the gastrointestinal smooth muscle and eventually lead to the occurrence of IBS symptoms such as abdominal pain and diarrhea [18].

3.7 Cholecystokinin CCK

CCK is the most abundant peptide in the brain. It excites and contracts the gallbladder, gastrointestinal smooth muscle, stimulates the secretion of organs such as the pancreas, stomach and small intestine, and participates in the occurrence of anxiety-like behaviors[19]. Related to maintaining the integrity of the intestinal mucosa,it can lower the visceral pain perception threshold, leading to the typical abdominal pain symptoms of IBS [20].

4. The regulatory effect of traditional Chinese medicine on brain-gut peptides

IBS can be called "diarrhea", "constipation" or "abdominal pain"according to its different symptoms. The disease is located in the large intestine and is closely related to the heart, liver, spleen, lung,and kidney. In “Seeking Truth in Medicine” , it is said that "woody depression is not reached, wind depression is not reached, wind wood impacts and spleen soil, then the pain is below the navel",modern doctors summarized “IBS Diagnosis and Treatment Experts on Irritable Bowel Syndrome (2017)” based on classics and clinical experience[21], suggesting that the pathogenesis is mostly liver depression and spleen deficiency, liver failure, liver and spleen disorder; spleen injury, weak spleen and stomach; spleen and stomach sleepy, damp-heat stagnation; spleen failure Abdominal distension, diarrhea, obstruction of the intestines, abdominal pain, intestinal conduction failure, constipation, long-term lack of spleen yang, involving the deficiency of kidney yang, the disease is lingering and difficult to heal. Treatment of irritable bowel syndrome based on the principle of syndrome differentiation can effectively improve the clinical symptoms of patients, and the changes in the level of brain-gut peptides in the body reflect the characteristics of the condition of patients with IBS to a certain extent [22]. Studies have found that VIP and 5-HT are positively correlated with the syndrome of liver stagnation and qi stagnation. The material basis of spleen deficiency and liver stagnation syndrome may be 5-HT and CRH, CGRP is positively correlated with IBS-D's spleen and stomach weakness syndrome, liver depression and spleen deficiency syndrome [23, 24].

4.1 Syndrome Differentiation and Use of Chinese Medicine Compound Decoction

4.1.1 Syndrome of liver depression and spleen deficiencyFor patients with liver-stagnation and spleen-deficiency syndrome,IBS-D is the main type. Abdominal pain is often aggravated by emotions, abdominal pain followed by diarrhea, and pain is reduced after diarrhea. Doctors often use the principle of soothing the liver and invigorating the spleen to make traditional Chinese medicine decoctions, or use classical prescription, Jiawei Tongxie Yao Fang,Baizhu Shaoyao San, etc. are commonly used clinically. Chen Jianlin et al. [25] found that Jiawei Tongxie Yao Fang can reduce the serum VIP and SP levels of IBS-D patients with liver depression and spleen deficiency. Wang Zhengfang et al. [26] used Shugan Jianpi Decoction combined with western medicine to treat patients with IBS-D. The clinical symptoms of the patients were improved, the serum 5-HT,CGRP, SP, and NPY levels were significantly reduced, and the disease recurrence rate was reduced. Lou Jing et al. [27] found that the addition and subtraction of Baizhu Shaoyao San combined with acupuncture can reduce the serum levels of 5-HT and CGRP in patients, effectively improve the clinical symptoms of IBS-D patients with liver depression and spleen deficiency, and improve the quality of life of patients.

4.1.2 Syndrome of weakness of spleen and stomachThe syndrome of spleen and stomach weakness usually develops from liver stagnation and spleen deficiency over time, mainly due to spleen and stomach weakness, frequent diarrhea after meals, loose stools and diarrhea, poor appetite and anorexia, etc. The treatment is based on the principle of invigorating the spleen and replenishing qi.Xie Yandong et al. [28] Using Shenlingbaizhu powder combined with compound glutamine enteric-coated capsules to treat patients with IBS, the clinical symptoms and inflammatory reaction of the patients were significantly reduced after treatment, the intestinal mucosal barrier function and 5-HT levels were significantly improved, and the medication was safe and reliable, and it is worthy of application and promotion. Wang Ruike et al. [29] found that Wumei decoction can treat patients with IBS spleen and stomach weakness by reducing plasma SP and CGRP levels, and the effect is significant.Gao Bin et al. [30] found that adding Jianpi Mixture to treat patients with IBS-D on the basis of conventional drugs can better increase the abundance of Veillonella, Cellobacteria, and Campylobacter in the intestinal tract, and shorten the time for symptom improvement.

4.1.3 Syndrome of spleen deficiency damp-heatThe spleen and stomach damp-heat syndrome is characterized by loose stools, uncomfortable after diarrhea, and often accompanied by burning or swelling in the anus. Professor Jiang Shisheng believes that the spleen-deficiency damp-heat syndrome is more common in IBS-D. Tan Hualiang et al. [31] used Professor Jiang Shisheng’s method to replenish qi Qilianchangning decoction with the principle of strengthening the spleen and clearing heat and removing dampness was used as the observation group to treat patients with IBS-D spleen deficiency and damp-heat syndrome. The control group took trimebutine maleate capsules and bifidobacterium quadruple viable tablets. In the observation group, the improvement of mental fatigue, appetite, abdominal pain, stool characteristics and frequency, 5-HT, VIP and SP levels were better than those in the control group.

4.1.4 Syndrome of spleen and kidney yang deficiency

The syndrome of spleen and kidney yang deficiency is characterized by cold pain in the abdomen, reduced temperature and pain, accompanied by cold limbs, etc., mostly due to a longer course of disease or caused by yang deficiency in the body. The treatment is based on warming and invigorating the congenital and acquired yang. He Qunfang et al. [32] applied Sishen Pills to treat patients with kidney-yang deficiency IBS-D. After treatment,the clinical symptoms improved significantly, and serum VIP, SP,and 5-HT levels were significantly improved. He Na et al [33] used Jianpi Huashi Decoction to treat patients with spleen and kidney yang deficiency type IBS-D. After treatment, the VIP level of the study group was significantly lower than that of the control group,and the NPY level was significantly higher than that of the control group. The clinical performance of the patients was significantly improved. It has a certain relief effect on anxiety, depression and other psychological emotions.

4.2 Application research of single Chinese medicine and its extract

Many scholars have found that the dosage of certain types of Chinese medicine components in the compound decoction will affect the efficacy of the decoction. Therefore, relevant experiments have been conducted on the mechanism of action of single Chinese medicine and its extracts in the treatment of IBS, including the correlation with brain-gut peptides, In sexual research, Liang Ruifeng et al. [34] found that Fangfeng can enhance the visceral hypersensitivity of IBS-D and regulate 5-HT and SP levels in plasma, hypothalamus and colon. However, which kind of the Fangfeng’s specific ingredient is effective, need to be further studied.Golden buckwheat has the effects of clearing away heat, detoxifying,strengthening the spleen and promoting dampness. Yan Jing et al. [35]found that the analgesic effect of golden buckwheat extract is better than that of ketotifen. The mechanism may be related to reduce the SP levels in IBS model rats and the visceral sensitivity.

4.3 The mechanism of action of traditional Chinese medicine external treatment

Traditional Chinese medicine external treatment because of its economic convenience, less adverse reactions, in the treatment of irritable bowel has been a good application, has certain advantages.These include external therapies such as acupuncture, acupoint application, ear-point pressing and massage. And for the simple use of drug therapy, whether traditional Chinese medicine or western medicine, combined with external treatment methods of traditional Chinese medicine on this basis, the therapeutic effect is more significant, and the regulation of brain-gut peptide levels is more positively assisted. The mechanism may be stimulated Acupuncture points, meridian conduction, drug penetration, etc. are related to the intervention of visceral allergic reactions, gastrointestinal tract activities, microbe-brain-gut axis and other therapeutic effects.

4.3.1 Acupuncture therapyAmong the external treatment methods, acupuncture has the most extensive application and research, which can relieve intestinal spasm, anti-inflammatory and pain relief, and regulate nerve and endocrine functions. Si Yuancheng et al. [36] acupuncture Tianshu,Zhongwan, Guanyuan, and Zusanli four points to treat IBS-D.After treatment, the weight of rats increased significantly, and the water content in feces, intestinal propulsion rate and NPY level were compared with the model the group is low, and effectively improves the diarrhea symptoms of model rats. Chen Suhua et al.[37] used Ziwu Liuzhu acupuncture method to treat patients with IBS-D. After treatment, the patients' serum 5-HT, VIP, SP levels and clinical symptoms were significantly improved, and the total effective rate of treatment was higher than that of the Linggui eight methods group. Control group. Yu Leimin et al. [38] found that the therapeutic effect of umbilical acupuncture is equivalent to that of Bacillus licheniformis. It can effectively improve the clinical symptoms and mental state of patients with IBS-D, and regulate the secretion of brain natriuretic peptide 5-HT, CGRP, SP, and VIP. Pei Lixia et al. [39] found that acupuncture can reduce the plasma levels of 5-HT, NPY and CGRP in patients with IBS-C, and improve the clinical manifestations of typical abdominal pain and abdominal discomfort in IBS. The treatment effect is better than that of the western medicine group. Tong Li et al. [40] moxibustion at Tianshu and Shangjuxu points in IBS-D rats and found that it may be a multitarget synergistic effect on the 5-HT signaling pathway in colon tissue to treat IBS-D.

4.3.2 Acupoint application and massage therapy

Traditional therapies, including acupoint application, ear-point pressing, massage, hot compress and music therapy with certain characteristics have been used in the treatment of IBS, and have certain therapeutic effects, but the specific therapeutic mechanism is related to brain-gut peptide research focused on acupoint application.Cao Guowu et al. [41] found that adding acupoint application to the treatment of IBS-D patients on the basis of conventional western medicine has a better effect than the treatment of western medicine alone. It can better improve the clinical manifestations of patients with abdominal pain, diarrhea, and bloating, and the levels of 5-HT,VIP, SP and CGRP were regulated. Zhang Wei et al. [42] performed abdominal massage to treat patients with IBS-C and found that the pathogenic factors of IBS were plasma CGRP, SP, VIP, CCK and other brain-gut peptides, and abdominal massage can significantly improve these indicators.

4.3.3 External therapy combined therapy

The combined use of various traditional Chinese medicine treatment methods can better play the role of curative effect, perform their duties and complement each other. Zhang Xingxing et al. [43]found that Jianpi Shugan Decoction combined with acupuncture can increase the number of intestinal bifidobacteria and lactobacilli,reduce the number of enterobacteria, and increase the resistance to colonization in the intestines, thereby effectively alleviating the clinical symptoms of IBS-D patients with liver depression and spleen deficiency. symptom. Chen Qian et al. [44] used acupuncture and salt-separated moxibustion to treat spleen-deficiency IBS-D, and the effect was significant. The possible mechanism is related to the regulation of serum 5-HT, CGRP, and CRF levels. Gu Wen et al [45]used acupoint application to treat IBS, and acupuncture at Taichong,Sanyinjiao, Tianshu, Shangjuxu, Zhongwan and other points at the same time. After treatment, they found that acupoint application combined with acupuncture reduced intestinal inflammation and internal organs. The hypersensitivity is weakened, and the disorder of the brain-gut axis is regulated. The mechanism is related to the reduction of the patient's serum 5-HT level.

5. Shortcomings and prospects

Although there are many animal and clinical trials based on the study of brain-gut peptides in the treatment of IBS with traditional Chinese medicine, there are still many shortcomings and the need for further research. ①At present, the research on IBS-D and liverstagnation and spleen-deficiency syndrome is more extensive, and there are relatively few studies on other types and syndrome types;②There are many clinical application studies of external therapy, but the research and exploration of its specific mechanism is relatively lacking; ③ The research of traditional Chinese medicine based on the microbe-gut-brain axis is not enough; ④The application research of single Chinese medicine and its extract is mostly in the stage of animal experiment, and further research is needed for its clinical efficacy.

In summary, the brain-gut axis and microbe-gut-brain axis theories provide new insights for the treatment of IBS. However, due to their complex relationship, there are still certain limitations in Western medicine treatment. Western medicine treatment is to relieve spasm and promote symptomatic treatment methods such as gastrointestinal motility and analgesia, but long-term use has instability and certain side effects. In recent years, both the oral decoction of traditional Chinese medicine and the external treatment of traditional Chinese medicine have gradually shown advantages in the treatment of IBS, but its modern mechanism of action is still in the process of continuous research. The foundation of the brain axis theory and the continuous strengthening of clinical research will open up ideas for the research on the treatment of IBS and its mechanism, and will provide more complete treatment methods for patients with IBS.