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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.

Received: 　　Accepted:

Corresponding author: 侯晓华　　E-mail: houxh@hust.edu.cn

DOI: 10.13294/j.aps.2022.0084

Citing This Article：

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