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草药治疗在功能性消化不良中的潜在价值：临床实践及机制

金玉, 侯晓华^*

华中科技大学同济医学院附属协和医院，武汉 430022

摘要

功能性消化不良（functional dyspepsia, FD）是临床实践和人群中最常见的功能性胃肠道疾病（functional gastrointestinal disorders, FGIDs）之一。它的特征是多种症状，包括上腹部疼痛和灼热、餐后饱腹感和早期饱腹感[1]。FD的病理生理学非常复杂，目前还没有完全弄清，但与肠-脑轴紊乱有关，导致运动功能障碍、内脏过敏、粘膜完整性受损、免疫激活和胃肠道微生物群改变。此外，由于FD的长期自然病史和频繁的波动症状，FD症状的控制额外困难。

有效的西医主要疗法包括质子泵抑制剂、H2组胺受体拮抗剂、促动力学、根除幽门螺杆菌和中枢神经调节剂。然而，西药不足以缓解所有症状。接受抑酸治疗的患者报告症状改善，从30%到70%不等，疼痛为主亚组比运动障碍样亚组更有可能获益。促胃动力剂主要用于餐后窘迫综合征，其反应率可变：多巴胺受体拮抗剂的有效率为59%-81%，5-羟色胺-4受体激动剂为32%-91%，毒蕈碱受体拮抗剂则为31%-80%，幽门螺杆菌感染患者进行根除治疗后，有效率为24%至82%。神经调节剂通常用于低剂量的难治性FD症状，随后出现各种治疗反应和不良反应。一般来说，当前治疗FD的疗效有限，患者的症状缓解率在27%至71%之间。在大多数情况下，单用单一靶向治疗很难改善FD患者的症状和生活质量，由于副作用，这些治疗的临床应用可能具有挑战性。

The potential of herbal therapies in patients with functional dyspepsia: clinical practice and mechanism

JIN Yu, HOU Xiao-Hua^*

Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China

Abstract

Functional dyspepsia (FD) is one of the most prevalent functional gastrointestinal disorders (FGIDs) in clinical practice and population. It is characterized by several symptoms including epigastric pain and burning, postprandial fullness and early satiety [1]. The pathophysiology of FD is too complex to be completely understood, but has been implicated with disordered gut-brain axis, leading to motility dysfunction, visceral hypersensitivity, damage of mucosal integrity, immune activation and alterations in gastrointestinal microbiota [2]. Besides, it takes additional difficulty to manage FD for its long-term natural history and frequent fluctuating symptoms [3].

  The main therapies in Western medicine with evidence of effectiveness include proton pump inhibitors, histamine-2 receptor antagonists, prokinetics, Helicobacter pylori eradication and central neuromodulators [3–6]. However, Western medicines are not sufficient to relieve all symptoms. Patients treated with acid suppressive therapy report symptom improvement, ranging from 30% to 70%, and the benefit is more likely in the pain predominant subgroup rather than dysmotility-like subgroup. Prokinetic agents, primarily used for postprandial distress syndrome, show variable responder rate: 59%–81% for dopamine receptor antagonists, 32%–91% for serotonin-4 receptor agonists and 31%–80% for muscarinic receptor antagonists. Helicobacter pylori eradication is recommended for infected patients, with an effective rate from 24% to 82%. Neuromodulators are often used for refractory FD symptoms in low doses, followed with various therapeutic response and adverse effects. In general, the efficacy of current therapies for FD is finite, with symptom reduction rate ranging from 27% to 71% among the patients [5]. On most occasions, it is difficult to achieve improvement of symptoms and quality of life in FD patients with the single-targeted treatments alone and clinical application of these treatments can be challenging owing to the side effects. 

The potential of herbal medicines to treat refractory diseases is increasingly recognized

To date, as alternative medicine, many herbal preparations have been proposed across countries, and evidence-based studies have shown their role in the treatment of many diseases, especially in FGIDs [7, 8]. For example, STW-5 (Iberogast), which is made from extracts of nine herbs, and commonly used in Europe, has shown therapeutic effects in FGIDs including FD [7, 9]. The herbal medications usually have broad pharmacological applications targeting to multiple etiologies of FGIDs, including altered intestinal sensory and motor function, inflammation, neurohormonal abnormality, which can partly explain their efficacy on a wide range of symptoms [7]. Herbal therapy is also common in Traditional Chinese Medicine (TCM) with a long history. In TCM, each kind of herbs has a property (“cold”, “hot”, “cool” or “warm”) and a flavor (“sweet”, “sour”, “bitter”, “acrid” or “salty”), which suggests its possible medicinal purpose. Multi-component medicinal herbs, therefore can hit multiple targets and then exert a synergistic therapeutic action [10, 11].  

Positive effect of the Qizhiweitong (QZWT) granules in patients with FD

Some TCM are effectively and widely used in clinic to treat FD, such as QZWT granules [12], Zhi-Zhu-Kuan-Zhong capsule [13], and Xiang-Sha-Liu-Jun-Zi granules [14]. A multicenter, randomized, double-blinded, controlled clinical trial has suggested that Zhi-Zhu-Kuan-Zhong capsule is superior to placebo in the treatment of postprandial distress syndrome with FD [13]. Lv et al. conducted a multi-center, randomized, double-blind, placebo- controlled clinical study to evaluate the efficacy and safety of Xiang-Sha-Liu-Jun-Zi granules and found it useful in significant symptomatic improvement in patients with FD [14]. Similarly, QZWT granules are clinically used for relieving liver stagnation, chest fullness and pain in the stomach and epigastrium, which is derived from Sinisan decoction in Shang Han Za Bing Lun. It is composed of Radix Bupleurum (Chai Hu in Chinese), Rhizoma Corydalis (Yan Hu Suo in Chinese), Fructus Aurantii (Zhi Qiao in Chinese), Rhizoma Cyperi (Xiang Fu in Chinese), Radix Paeoniae Alba (Bai Shao in Chinese) and Radix Glycyrrhizae (Gan Cao in Chinese). This formula is an ancestral formula for relieving depression in the liver and harmonizing the liver and spleen. 

  A randomized, double-blind, multicenter, placebo- controlled trial of QZWT granules on postprandial distress syndrome-predominant FD was finished by our teams [12]. The study showed that: 1) the total effective rate and dyspeptic symptom relieving scores in the QZWT granules group were significantly higher than those in the placebo group, no matter during the treatment or follow-up period; 2) The severity and frequency of each dyspeptic symptom and anxiety scores in the QZWT granules group were all significantly lower than those in the placebo group; 3) QZWT granules did not have more adverse effects than the placebo. The results have shown that QZWT is a potentially well-tolerated and effective treatment for FD. 

Action of QZWT granules through bidirectional effects

The mechanism of TCM undoubtedly warrants further investigation. Zhou et al. reported in this issue that QZWT granules have bidirectional effects on gastric gastric electricity and motility in vivo and in vitro, and a significant inhibitory effect on acute inflammation in rats with gastroparesis [15]. As early as the Jin and Yuan dynasties of ancient China, the bidirectional property of TCM was recorded in the classic work Medicine Origin (Yi Xue Qi Yuan in Chinese). For instance, the Fructus Aurantii (Zhi Qiao in Chinese) and Magnolia Officinalis (Hou Pu in Chinese) can bidirectionally regulate gastrointestinal motility [16].  Some other herbal medicines also showed bidirectional effects in clinic, for instance, Panax ginseng C. A. Meyer showed bidirectional regulation of immune function and the central nervous system; Astragalus membranaceus can regulate blood pressure and immune function bidirectionally; and Rheum officinale Baill exerts bidirectional effects on blood circulation and hemostasis, gastrointestinal motility and immune function [11]. The mechanisms underlying the bidirectional effects of TCMs are largely attributed to the complexity of herbal constituents, dosage differences, the processing of herbal medicine, and compatibility of medicines, the physiological conditions of patients and adaptogenic effects [11].

  A serum metabonomic method has been established to investigate the QZWT components [17]. It was found that four components present good prokinetic effects, including Bupleurum polysaccharide, Citrus aurantium flavonoid, Citrus aurantium essential oil and Cyperus rotundus flavonoids. Then 5 potential biomarkers primarily involved in 5 metabolic pathways were regulated by these components and entire QZWT. The results suggest that the mechanisms of QZWT promoting gastrointestinal motility involve multi-component, multi-target, and multi-pathway, which fully reflects the compounds’ synergistic actions of TCM. To achieve the therapeutic goal of refractory FD, extensive and high-quality studies on the pharmacological mechanisms and clinical effects of these herbal medications are required.

Conclusion and future direction

Currently available therapies aiming at a single target show limited and variable efficiency and lack long-term effectiveness and safety. Furthermore, the presently used pharmacological treatment options for FD also show limited and variable efficiency. Therefore, novel effective drugs are urgently needed. Increasing evidence demonstrates that herbal medicine is effective in the treatment of FD. Its use as a treatment option in addition to Western medicine is worth trying, especially for those who failed in the treatment with Western medicine. However, the lack of research on the mechanism of action of herbal medicines for FD has limited their clinical application. For those herbs which can be extracted as single component, it is important to explore mechanisms of therapeutic effect, and pay attention to whether the component can exert similar efficacy of herbal medicine in future research. In addition, for those herbs that cannot be isolated as single component, although it is difficult to clarify all mechanisms, we need to focus on limiting their adverse effects and keeping multi-target efficacy to improve various symptoms at the same time. Finally, due to the differences in ethnicity, region, environment and lifestyle between Chinese and Westerners, more evidence-based medical studies are needed in the future to determine whether TCM has the same efficacy for Westerners. As our understanding of the herbal medications advances, it is very likely that we can effectively treat FD using a combination of TCM and Western medicine.

收稿日期：　　录用日期：

通讯作者：侯晓华　　E-mail: houxh@hust.edu.cn

DOI: 10.13294/j.aps.2022.0084

引用本文：

金玉, 侯晓华. 草药治疗在功能性消化不良中的潜在价值：临床实践及机制[J]. 生理学报 2022; 74 (5): 682-684.

JIN Yu, HOU Xiao-Hua. The potential of herbal therapies in patients with functional dyspepsia: clinical practice and mechanism. Acta Physiol Sin 2022; 74 (5): 682-684