Potential Mechanism and Application of Strengthening the Spleen, Clearing Heat and Dampness in Treatment of Gastroesophageal Reflux Disease

XIE Jing-yi (謝璟儀), ZHONG Min (鐘 民), CHE Hui (車(chē) 慧), ZHAO Ying-pan (趙迎盼)

Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China

Correspondence to: ZHAO Ying-pan, Tel: 010-62835101. E-mail: zypzyp1984@163.com

Supported by: Nursery Project of Xiyuan Hospital, China Academy of Chinese Medical Sciences - Peripheral mechanism of mast cell activation of PAR2/TRPV1 pathway in NERD esophageal hypersensitivity and the intervention of Jianpi Qinghua Granules (2019XYMP-48)

ABSTRACT Gastroesophageal reflux disease (GERD) is one of refractory digestive disease in clinic characterized by high prevalence, complex and recurrent symptoms. Traditional Chinese medicine(TCM) has a significant effect on the treatment of GERD. Spleen deficiency and damp-heat syndrome becomes one of the main syndrome patterns of GERD adapting with the changes of modern lifestyle.Although the therapy of strengthening the spleen, clearing heat and dampness is widely used in treatment of GERD, further studies still need to be conducted. The article comprehensively analyses the theoretical basis, mechanism and clinical efficacy of the therapy in order to provide more ideas for clinical treatment.

KEYWORDS Gastroesophageal reflux disease; Spleen deficiency and damp-heat syndrome; TCM

GERD is a common refractory digestive disease in clinic which is characterized by high prevalence, complex and recurrent symptoms.Multiple factors such as esophageal-gastric motility abnormality, reduced esophageal clearance ability,esophageal mucosal barrier dysfunction, visceral hypersensitivity, decreased gastric emptying capacity and so forth are involved in the pathogenesis of GERD. The complexity of pathogenesis limits the efficacy of proton pump inhibitors (PPIs). As clinical studies showed, 37.9% of patients with non-erosive reflux disease (NERD) failed to relieve symptoms after receiving 6 weeks of standard-dose PPIs treatment[1], and 2/3 of GERD patients had recurrent or aggravating symptoms and reappearance of endoscopic mucosal erosion after stopping PPIs[2].

TCM has significant advantages of multiple targets, individualization, and less adverse reactions in the treatment of GERD aiming to solve the current bottleneck of treatment. Large amount of records of GERD related symptoms has been found in ancient medical books. The location of GERD is mainly in the esophagus and stomach, and is closely related to the dysfunction of the liver, gallbladder, spleen and other organs in TCM[3]. With the tremendous changes in lifestyle and diet nowadays, overweight and obesity have become important factors leading to the increase in the incidence of GERD in Asia-Pacific region[4]. The distribution of the syndrome patterns of GERD has also changed. Compared with the previous consensus, 'Gastroesophageal Reflux Disease TCM Expert Consensus (2017)'adds spleen deficiency and damp-heat syndrome to the common syndrome patterns, indicating that the syndrome conforms to the pathogenesis especially for modern people and is universal in clinical practice.The method of strengthening the spleen, clearing heat and dampness is relatively established on the syndrome pattern of spleen deficiency and dampheat syndrome. However, the theoretical basis,mechanism and clinical efficacy of strengthening the spleen, clearing heat and dampness in treatment of GERD still need to be explored.

Theoretical Basis of Strengthening the Spleen,Clearing Heat and Dampness in the Treatment of GERD

Ancient physicians believed that 'heat' was the main pathogenesis feature of GERD, which mainly involved liver, stomach, and lungs. In early ancient books, the stomach and liver were mentioned and discussed. There is a connotation inHuangdi Nei Jing(《黃帝內(nèi)經(jīng)》) 'All syndromes characterized by vomiting and acid regurgitation are associated with heat.' Physician Wang Kentang in the Ming Dynasty extended the location of GERD to the lung, liver and spleen that the liver fire flaring up and weaken lungs and spleen. Heat is often compared with dampness and affect each other. Physician Zhu Danxi proposed that GERD related symptoms were caused by endogenous dampness and heat. As dampness is resulted from the failure of the transformation of the spleen, the weakness of the spleen and stomach is the basic pathogenesis of GERD. To sum up, the syndrome of spleen deficiency and damp-heat reflects the complexity of syndrome differentiation of GERD that spleen deficiency represents insufficiency while damp and heat represent excess. Spleen deficiency leads to the disharmony of ascending and descending of qi. The blockage of qi forms damp and heat, and finally result in adverse of stomach qi and cause the disease.

Latest studies of syndromes and the distribution of syndrome elements have also confirmed the significant position of spleen deficiency and dampheat syndrome in GERD. Zhang Jiao et al.[5]found that the most common syndromes of GERD were liver-stomach discordant syndrome, spleen deficiency and damp-heat syndrome, liver-stomach and stagnation-heat syndrome. Study of Li Peicai et al.[6]showed that patients of GERD with liver and stomach stagnation-heat syndrome, spleen and stomach weakness syndrome, and spleen and stomach damp-heat syndrome accounted for nearly 50% of total. And among the main syndromes,the overall proportion of heat, qi deficiency and dampness reached 65% of total. Liu Ting[7]analyzed the syndrome of 130 patients with reflux esophagitis(RE) and found that spleen deficiency and dampheat syndrome accounted for 27.69%, preceded only by liver-stomach discord. Lai Yufei et al.[8]analyzed the correlation between the degree of mucosal lesions and the syndrome patterns in 453 patients with RE, and found that the spleen and stomach damp-heat syndrome is common in patients of Los Angeles graded A to C, while the spleen and stomach deficiency syndrome is common in patients of Los Angeles graded D.

Though understandings of the pathogenesis of GERD are different among TCM physicians, factors such as deficiency, heat, phlegm and dampness are well recognized. In the past, the differentiation and treatment of GERD were mostly carried out from liver-stomach discord and liver-stomach stagnation.In recent years, the role of spleen deficiency in the occurrence and development of GERD has gradually attracted attention. Studies have shown that the incidence of typical manifestations of spleen deficiency syndromes such as anorexia, fatigue,abdominal distension, bloating, abdominal pain,and loose stools accounts for 52.89% of the total frequency of the 10 most common symptoms of GERD[9]. 'Gastroesophageal Reflux Disease TCM Expert Consensus (2017)' also pointed out that insufficient endowment and weakness of the spleen and stomach are the basic pathogenesis of GERD.Deficiency of spleen and stomach leads to abnormal movement of qi and failure of transformation of the spleen, and result in qi inversion, fire depression,damp resistance which can aggravate spleen deficiency in turn and finally carried out as GERD[3].

Potential Mechanism of Strengthening the Spleen, Clearing Heat and Dampness in Treatment of GERD

The pathogenesis of GERD is the result of the unbalance between reflux on esophageal mucosa and anti-reflux barrier defense[10]. Acid, digestive enzymes, bile and other refluxes can directly cause the necrosis of esophageal epithelial cells or destroy the connexin between epithelial cells[11], resulting in increased esophageal mucosal permeability, and can induce cytokine-mediated immune inflammatory response promoted damage to the esophageal epithelial barrier[12]. Anti-reflux defense mechanisms mainly contain three defensive lines: anti-reflux barrier, esophageal cavity clearance and esophageal mucosal barrier[13]. The damage of the above defense lines induces reflux events, making the esophageal mucosa more vulnerable to regurgitant attack.

A study of Fu Bin et al.[14]found that patients with NERD showed minimal changes in the cardia under the endoscopy, and the proportion of minimal changes in patients with spleen and stomach damp-heat syndrome was higher than other syndrome patterns.The therapy of strengthening the spleen, clearing heat and dampness has the effect of inhibiting inflammatory factors and improving esophageal mucosal damage.A study of Shen Hui et al.[15]showed that Yiqi Chupi Decoction (益氣除痞方), which can strengthening the spleen and smooth qi, can effectively reduce serum level of IL-1 and TNF-α in RE patients with spleen deficiency and dampness syndrome, and improve clinical symptoms and esophageal mucosal erosion.Xiao Jiao et al.[16]found that Hezhong Jianpi Decoction(和中健脾方), aiming to strengthening the spleen and harmony the stomach, can down-regulate the expression of IL-6, IL-8, and nuclear factor kappa B p65 in serum of model rats, and thereby reducing esophageal inflammation.

Huang Di Nei Jingstates that 'the spleen governs the flesh', which meets the modern gastrointestinal dynamics theory that the rhythmic secretion of the digestive organs and the migrating compound movement of the digestive tract from top to bottom are the basis of digestion and nutrient absorption. It also confirms the physiological characteristics of the stomach as descending and smooth[17]. Wang Hongmei et al.[18]found that the relaxation time of the lower esophageal sphincter in patients with spleen deficiency syndrome was prolonged, which affected the contraction function of the lower esophageal sphincter, and declined the peristaltic function representing by shortening the maximum duration of the esophageal contraction wave and lowering the peristaltic conduction velocity.Spleen-invigorating drugs have the effect of promoting gastrointestinal motility. Sijunzi Decoction (四君子湯),a spleen strengthening decoction, can improve the kinase content of myosin light chain in gastric antrum and jejunum smooth muscle cells in rats with spleen deficiency by adjusting the distribution of food in the proximal and distal stomach[19]. Sijunzi Decoction(四君子湯) may also improves gastric receptive relaxation and delayed gastric emptying[20].

In addition, abnormal brain-gut interaction and disorder of brain-gut peptide secretion cause disorder of digestive tract motility and increase visceral sensitivity.Huang di Nei Jingstates that 'the spleen contains nutrient qi and the spirit is attached to nutrient qi'. The deficiency of the spleen results for disability of limbs and disharmony of the five organs.' Ma Xiangxue et al.[21]believed that brain-gut peptides are transferred and transported by spleen and distributed in the brain and intestines with the movement of qi. The normal secretion of brain-gut peptides depends on the function of the spleen of transformation and transportation.Li Rongping et al.[22]found that the therapeutic effect of soothing the liver and strengthening the spleen and the stomach in patients with refractory GERD may be related to the down-regulation of protease activated receptor-2 (PAR-2) and transient receptor potential family vanilloid subtype 1 (TRPV1) expression which was related to reducing esophageal hypersensitivity.Qiu Xinping et al.[23]established a rat model of NERD with ovalbumin and aluminum hydroxidebased sensitization combined with esophageal acid perfusion. The intervention of Jiangni Qingre Huazhuo Decoction (降逆清熱化濁方)can inhibit the expression of calcitonin gene-related peptide in esophageal tissue of rats with NERD and down-regulates esophageal hypersensitivity. Ren Ping[24]found that rats with spleen deficiency syndrome have low gastric emptying rate, slow gastric rhythm, declined amplitude and movement and other gastrointestinal motility disorders.Sijunzi Decoction (四君子湯) can promote gastric emptying of rats with spleen deficiency by regulating secretion of motilin, somatostatin and cholecystokinin in hypothalamus and plasma.

Application of Strengthening the Spleen,Clearing Heat and Dampness in Treatment of GERD

Huang lian Decoction (黃連湯) was recommended as the first choice prescription for GERD patients with spleen deficiency and dampheat syndrome in 'Gastroesophageal Reflux Disease TCM Expert Consensus (2017)'. In a clinical study conducted by Feng Minxiao et al.[25], 40 NERD patients with spleen deficiency and damp-heat syndrome were enrolled and given rabeprazole capsules and Huanglian Decoction (黃連湯)respectively for 4 weeks. Result showed that the total clinical effective rate of Huanglian Decoction (黃連湯)group was significantly higher than that Rabeprazole.Huanglian Decoction (黃連湯) effectively alleviated the main symptoms of acid reflux, retrosternal pain or discomfort, belching reflux and other major symptoms as well as improved all dimensions of SF-36 Quality of Life Scale. The incidence of adverse reactions such as nausea and diarrhea was less than that of rabeprazole. The study of Li Yao et al.[26]showed the total clinical effective rate and endoscopic effective rate was 97% and 95% respectively adopting Huanglian Decoction (黃連湯) adding pantoprazole and domperidone.

Academician Dong Jianhua's theory of Dredging-Descending holds that[26]the physiological disorder of the stomach obeying the principle of harmony by descending may lead to the descending or adverse rising of stomach qi, failing to send up essential substances so forth, further causing or aggravating phlegm turbidity, pathogenic dampness,blood stasis and so forth and aggravating blockade of qi movement. Professor Tang Xudong put forward the theory of Dredging-Descending and create the'New Eight Principles' which meets the physiological and pathological characteristics of the spleen and stomach[27]. Jianpi Qinghua Granules (健脾清化顆粒) is an empirical prescription formed by Professor Tang Xudong under the guidance of Academician Dong Jianhua's theory of Dredging-Descending.The prescription is composed of 11 herbs including Codonopsis, Atractylodes Rhizome, Scutellaria baicalensis Georgi and so on with the functions of strengthening the spleen, regulating qi and clearing heat and dampness in order to inhibit stomach acid reflux. One of our multi-center, randomized, doubleblind, double-simulation clinical study confirmed that Jianpi Qinghua Granules (健脾清化顆粒) combined with low-dose omeprazole can significantly relieve main symptoms and improve quality of life in patients of NERD with spleen deficiency and dampheat syndrome.

Summary

Spleen deficiency and damp-heat syndrome is one of the common syndrome patterns of GERD,which fully reviews the pathogenesis of GERD characterized by the combination of deficiency and excess. Recent studies based on the pathological mechanism of GERD have confirmed that the therapy of strengthening the spleen, clearing heat and dampness is of great significance in GERD treatment,which has the effects of inhibiting inflammation,improving esophageal motility, regulating gastrointestinal hormone levels, and reducing visceral sensitivity. However, the complexity of the syndrome pattern also brings challenges to further research. At present, there are few clinical studies aiming to GERD with spleen deficiency and damp-heat syndrome.Insufficient evaluation standard and imperfect study quality control limit the clinical application. In addition, spleen deficiency and damp-heat syndrome is often split into single syndrome pattern of spleen deficiency, dampness, and heat or a combination of two syndrome patterns in former studies. There is a lack of research on the overall syndrome of spleen deficiency and damp-heat syndrome as well as mechanism of the syndrome combined with diseases. Moreover, establishing animal models that is compatible with the pathogenesis of GERD and the characteristics of spleen deficiency and dampheat syndrome is the basis for further pathology and pharmacodynamic researches.